NM_000059.4(BRCA2):c.5222_5225del (p.Ser1741fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 8, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001183270.13

Allele description [Variation Report for NM_000059.4(BRCA2):c.5222_5225del (p.Ser1741fs)]

NM_000059.4(BRCA2):c.5222_5225del (p.Ser1741fs)

Gene:

BRCA2:BRCA2 DNA repair associated [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

13q13.1

Genomic location:

Preferred name:

NM_000059.4(BRCA2):c.5222_5225del (p.Ser1741fs)

Other names:

5450del4

HGVS:

NC_000013.11:g.32339577_32339580del
NG_012772.3:g.29098_29101del
NM_000059.4:c.5222_5225delMANE SELECT
NP_000050.3:p.Ser1741fs
LRG_293:g.29098_29101del
NC_000013.10:g.32913711_32913714del
NC_000013.10:g.32913714_32913717del
NM_000059.3:c.5222_5225delGTAA
U43746.1:n.5450_5453delGTAA
p.S1741TfsX35

Links:

Breast Cancer Information Core (BIC) (BRCA2): 5450&base_change=del GTAA; dbSNP: rs80359498

NCBI 1000 Genomes Browser:

rs80359498

Molecular consequence:

NM_000059.4:c.5222_5225del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001348955	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 15, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002640620	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jan 8, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 29446198, 31528241, 31721094 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001348955

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 15, 2020)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002640620

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jan 8, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations.

Rebbeck TR, Friebel TM, Friedman E, Hamann U, Huo D, Kwong A, Olah E, Olopade OI, Solano AR, Teo SH, Thomassen M, Weitzel JN, Chan TL, Couch FJ, Goldgar DE, Kruse TA, Palmero EI, Park SK, Torres D, van Rensburg EJ, McGuffog L, Parsons MT, et al.

Hum Mutat. 2018 May;39(5):593-620. doi: 10.1002/humu.23406. Epub 2018 Mar 12.

PubMed [citation]

PMID:: 29446198
PMCID:: PMC5903938

See all PubMed Citations (4)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001348955.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This variant deletes 4 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Ambry Genetics, SCV002640620.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The c.5222_5225delGTAA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at positions 5222 to 5225 causing a translational frameshift with a predicted alternate stop codon (p.S1741Tfs*35). This alteration was identified in 3/539 families from Pakistan with early onset and/or familial breast cancer (Rashid MU et al. Hered Cancer Clin Pract, 2019 Sep;17:27). This alteration was also identified in a cohort of 1764 Chinese lung cancer patients, specifically in a 42 year old male with squamous cell carcinoma (Tian P et al. Pathol. Oncol. Res., 2019 Nov). Furthermore, this alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 17, 2024

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